Designer Antibodies and HIV:A Step Towards a Cure

Angel Pichardo, Beau Smith, Halle Burns, Jake Harris

Intro● CART has dramatically reduced the number of AIDS-related deaths and has

increased the life expectancy of those infected with HIV.

● A variety of approaches have been attempted to fully eradicate the virus but the

persistence of HIV reservoirs has always allowed for viral RNA levels to rebound.

● One approach, involves shocking CD4 cells into activating the latent HIV virus

and using another drug to destroy the activated viruses. Has only been performed

in test tubes.

● This novel approach involves in the use of bispecific antibodies that bind to CD3

receptors and HIV proteins.

● “Stuffs prey into lion’s mouth”

The StructuresCD3 Receptor

● Involved in cytotoxic

T-cell activation

● Part of T-cell

Receptor (TCR)

found on all T-cells

https://en.wikipedia.org/wiki/CD3_(immunology)

The StructuresHIV-1 Env Proteins

● gp120

● gp41

● Displayed on surface

of CD4+ cells when

infected

https://commons.wikimedia.org/wiki/File:HI-Virion-en.png

The StructuresAntibodies (Sung et al.)

● 2-Fab regions

● anti-CD3 antigen-binding

site

- Derived from hXR32

(humanized anti-CD3ε mAb)

● anti-HIV antigen-binding

site

- A32 binds to gp120

- 7B2 bind to gp41

Figure 1 from Sung et al. (2015)

The StructuresAntibodies (Pegu et al.)

● 2-Fab regions

● Anti-CD3 antigen-binding site

- Single chain variable fragment

(scFv) on light chain

● anti-HIV antigen-binding site

- VRC07 protein

- Targets gp120

- Highly active mutation

(G54W)

- Binds to HIV-1-Env proteins

Figure 1a from Pegu et al. (2015)

Mechanism: Dual Affinity Re-targetingCD3: Plays several roles in the elimination of latent CD4+ cells:

A. Induces proliferation of CD4 cells via CD3 binding

B. Helps bridge CD4 and CD8 cells via CD3 binding

C. Provides necessary stimulation for ANY CD8 lysis of CD4 cell

gp41 and gp120:

A. Help bridge CD4 and CD8 cells via binding of gp41 or gp120 of infected cells

When both occur simultaneously, the product is greater than the sum of the parts:

A. More latent CD4s are activated and healthy CD4s are recruited as effectors

Prospects❖ 1999 Study: Not so great

➢ Over activation

■ Inflammatory reaction, Kidney failure and other organ damage, Seizures

➢ Serious complications

❖ New Study: Promising, but no human trials

➢ DART

➢ New antibodies are bispecific vs. antibodies with two arms

➢ Caution against possibility of over activation of T cells

Issues With The New Studies ❖ Mouse trials

➢ One of the studies was conducted in Mice

■ Xenogenic Mouse Antigens → Chronic Hyperstimulation

■ Engrafted Human T Cells Compared To Those Educated Completely In Humans → Antigen

Specificity

■ HIV-1 interactions with different cell types

● Variability in engraftment and levels of human and murine cells

❖ Target Cells

➢ Potential Facilitation of Synapse Between Infected and Uninfected CD4 TCells

Access❖ Cost of treatment

❖ Justice

➢ Geography

➢ Status

❖ Human Trials

Ethics❖ Human Trials

➢ When is it safe

➢ What is the sample population

➢ Who would volunteer

❖ AIDS is no longer a death sentence

➢ Treatment

❖ Prevention or Cure

➢ PrEP

➢ Resources

Complications and Barriers❖ What cells make up the HIV reservoir

➢ Unknow aspect → Are all reservoirs depleted?

❖ HIV/AIDS Community

➢ Skepticism

➢ Fear

➢ Misunderstanding

Works Cited

Cohen, Jon. "Designer Antibodies May Rid Body of AIDS Virus." Science Magazine. American Association For

The Advancement of Science, 20 Oct. 2015. Web.

Sung, J. et al. Dual-Affinity Re-Targeting proteins direct T cell–mediated cytolysis of latently HIV-infected cells.

J Clin Invest. 2015;125(11):4077–4090. doi:10.1172/JCI82314.

Pegu, A. et al. Activation and lysis of human CD4 cells latently infected with HIV-1. Nat. Commun. 6:8447 doi:

10.1038/ncomms9447 (2015).

"PRE-EXPOSURE PROPHYLAXIS (PrEP)." AIDS.gov. U.S. Department of Health and Human Services, n.d. Web. 29 Apr. 2016.